Inflammatory diseases such as rheumatoid arthritis, asthma and hepatitis are among the leading causes of death and disability in the world. Chronic inflammation contributes to the development of degenerative diseases including cancer (1), cardiovascular diseases (2) and neuro-degenerative disorders (3). During inflammation, various eicosanoids derived from arachidonic acid (AA) play a key role in mediating inflammatory response (4). For instance, prostaglandin E2 (PGE2), which is synthesized from cyclooxygenase (COX)-catalyzed oxidation of AA, is believed to cause pain and fever (4, 5), as well as activate cytokine formation (6). PGE2 can be produced by either the constitutive form (COX-1) or the inducible form (COX-2) of cyclooxygenase (7). In most inflammatory conditions, COX-2 is up-regulated and is the primary enzyme responsible for the formation of pro-inflammatory PGE2 (7). Leukotriene B4 (LTB4), another oxidized product derived from AA through the 5-lipoxygenase-catalyzed pathway, is one of the most potent chemotactic agents (8). Because of the central roles of PGE2 and LTB4, COX-2 and 5-lipoxygenase have been recognized as key targets for the drug therapy in inflammation-associated diseases. In particular, COX-2 inhibitors, which are classified as non-steriod anti-inflammatory drugs (NSAIDs), have been proven to be effective in attenuating inflammatory response and beneficial for certain inflammation-associated diseases (9).
Vitamin E consists of eight compounds; four tocopherols (alpha-, beta-, gamma-, and delta-) and four tocotrienols (alpha-, beta-, gamma-, and delta-). Among them, only alpha-tocopherol has been extensively studied. Gamma-tocopherol (gamma-T) is the major form of vitamin E in the US diet. However, it has drawn little attention compared with alpha-tocopherol, the primary form of vitamin E found in most supplements. Delta-tocopherol (delta-T) is another form of vitamin E that is rich in some food sources (often found with gamma-tocopherol, e.g. in soybeans and soybean oil). Tocotrienols are mainly abundant in palm oil.
We recently found that gamma-tocopherol (gamma-T), and its physiological metabolite, 2,7,8-trimethyl-2-(b-carboxyethyl)-6-hydroxychroman (gamma-CEHC), inhibits COX-2-catalyzed formation of PGE2, as assayed in lipopolysaccharide-stimulated macrophage and interlukin-1b activated epithelial cells (10; see also our review, 18). This indicates that gamma-T and its metabolite may have anti-inflammatory properties that are similar to those of NSAIDs. In contrast, alpha-tocopherol (alpha-T), the predominant form of vitamin E in the tissues and most supplements, is much less effective in this regard (10). It was not clear, however, whether gamma-tocopherol would reach significant levels in tissues to exert significant effects in vivo.
Here we show that this bioactivity of gamma-T is demonstrable in vivo, and more importantly, establish that there are three pathways by which gamma-T inhibits inflammation, and indicates that gamma-T has superior and supplemental pharmaceutical potential over the commonly used cyclooxygenase inhibitors. We disclose the use of gamma-T, delta-T, and their corresponding metabolites (gamma-CEHC, Delta-CEHC), as well as combinations of gamma-T and delta-T, and these tocopherols with gamma-tocotrienol or delta-tocotrienol, in the form of supplements or drugs, particularly in combination with existing drugs such as NSAIDs to treat inflammation, particularly inflammatory diseases such as arthritis, bowel diseases, and asthma. These subject medicaments can also be used to treat and prevent chronic diseases associated with inflammation such as cancer and cardiovascular disorders.
U.S. Pat. Nos. 6,204,290; 6,242,479; 6,410,589; and 6,239,171 appear relevant to this disclosure.